1. Field of the Invention
This invention relates to an improved process for preparing 1-methylindazole-3-carboxylic acid (1-MICA) of formula (I):

This invention also relates to the preparation of the antiemetic drug Granisetron {endo-1-Methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide} and its hydrochloride salt, which drug is disclosed in EP 200,444 (Beecham Group), using the process of the present invention for preparing 1-MICA.
2. Description of the Related Art
The synthesis of 1-MICA has been described by K. v. Auwers and R. Dereser: Chem. Ber. 1919, 52, 1340–1351. This method involves methylation of the compound of formula (II) with iodomethane in methanol in the presence of sodium methoxide obtained in situ by reaction of sodium with methanol. 1-MICA is a known intermediate, which is useful for the production of the antiemetic drug Granisetron (endo-1-Methyl-N-(9-methyl-9-azabicyclo[3.3.1]non-3-yl)-1H-indazole-3-carboxamide) and its hydrochloride salt. See, e.g., EP 0200444.
A mixture of 1- and 2-isomers (compounds III and IV) with a domination of 1-isomer (III) is obtained in the procedure.

Crystallization of the mixture from petroleum ether gives a pure 1-isomer. 1-MICA is obtained by hydrolysis of methyl ester III. This is an undesirable route as it involves the use of sodium metal for the generation of sodium methoxide. The use of sodium metal in industrial scale is disadvantageous for safety reasons. In addition, the selectivity for 1-MICA in this process is only ca 2:1 (relative to 2-MICA), and the purification and hydrolysis steps result in low yields (ca 30%).
An alternative process involving methylation of the compound of formula (V) is described by V. Rousseau and H. G. Lindwall, JACS 1950, 72, 3047.

This process also results in a mixture of isomers and involves purification and hydrolysis steps.
A one stage highly selective process for producing 1-MICA has been described in EP 323, 105 (Beecham Group). The process comprises the reaction of a methylating agent with indazole-3-carboxylic acid (ICA) of formula (VI) in a polar solvent in which is dissolved an alkali metal alkoxide.

Preferable solvents are anhydrous lower alkanols. The alkali metal alkoxide is usually formed in situ by reaction of alkali metal with the lower alkanol solvent. 1-MICA is obtained in high yield. However, hydrogen evolves at in situ preparation of alkali metal alkoxide and it makes this process hazardous on an industrial scale preparation of 1-MICA. In addition, during the course of the reaction methyl esters of 1-MICA and 2-MICA are formed (ca. 10%). The reaction mixture obtained using this procedure contains at the end of reaction ca 7% 2-MICA.